Elinzanetant

LYNKUET is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause. LYNKUET is a neurokinin 1 (NK1) and neurokinin 3 (NK3) receptor antagonist indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. ( 1 )

Capsules: 60 mg, opaque red, oblong, soft, gelatin capsules, with white printing of "EZN60". Capsules: 60 mg ( 3 )

LYNKUET is contraindicated in pregnancy. Exposure to LYNKUET may cause pregnancy loss or stillbirth when administered during pregnancy [see Use in Specific Populations (8.1 , 8.3) ] . Pregnancy. ( 4 )

CNS Depressant Effect and Daytime Impairment: Advise patients about the potential for somnolence and other nervous system effects. Advise patients who experience these effects to refrain from driving or engaging in hazardous occupations or activities until the effects have resolved ( 5.1 ) Hepatic Transaminase Elevations: Perform bloodwork prior to initiation of LYNKUET to evaluate for hepatic function and injury. Do not start therapy if serum transaminase concentration is equal to or exceeds two times the upper limit of normal (ULN) or if the total bilirubin is equal to or exceeds two times the ULN. Perform follow-up evaluations of hepatic transaminase concentration 3 months after initiation. Advise patients to discontinue LYNKUET immediately in case of signs or symptoms suggesting liver injury. ( 5.2 ) Risk of pregnancy loss: May cause pregnancy loss or stillbirth when administered during pregnancy. Exclude pregnancy in females of reproductive potential prior to initiating LYNKUET. Discontinue if pregnancy is confirmed ( 5.3 ) Risk of seizure ( 5.4 )

5.1 Central Nervous System (CNS) Depressant Effect and Daytime Impairment In the three OASIS trials, nervous system effects (including somnolence, fatigue, vertigo, dizziness and presyncope) occurred in 11.9% of patients on LYNKUET compared to 3.5% on placebo. [see also Adverse Reactions (6.1) ]. Advise patients about the potential for somnolence and other nervous system effects. Advise patients who experience these effects to refrain from driving or engaging in hazardous occupations or activities until the effects have resolved [see Clinical Studies (14.3) ].

5.2 Hepatic Transaminase Elevations Elevations in serum transaminase (ALT and/or AST) concentrations equal to or greater than three times the ULN occurred in 0.6% of patients receiving LYNKUET and 0.4% of patients receiving placebo up to 12 weeks in three clinical trials. Perform baseline bloodwork (including ALT, AST, alkaline phosphatase, and total and direct bilirubin) prior to initiation of LYNKUET to evaluate for hepatic function and injury. Do not start therapy if serum transaminase concentration is equal to or exceeds two times the ULN or if the total bilirubin is equal to or exceeds two times the ULN. Perform follow-up evaluations of hepatic transaminase concentration 3 months after initiation of therapy. Advise patients to discontinue LYNKUET immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain). Discontinue LYNKUET if transaminase elevations exceed five times the ULN or if transaminase elevations exceed three times the ULN and total bilirubin exceeds two times the ULN. Exclude alternative causes of hepatic laboratory test elevations.

5.3 Risk of Pregnancy Loss LYNKUET is contraindicated for use in pregnancy [see Contraindications (4) ]. Findings from animal studies suggest that LYNKUET can cause pregnancy loss or stillbirth. Exclude pregnancy in females of reproductive potential prior to initiating LYNKUET. Advise females of reproductive potential to use effective contraception during treatment with LYNKUET and for 2 weeks after stopping LYNKUET [see Use in Specific Populations (8.1 , 8.3) ] .

5.4 Risk of Seizure Seizure was reported in patients taking LYNKUET [ see Adverse Reactions (6.1 , 6.2) ]. In addition, convulsions were observed in studies conducted in male and female rats [see Nonclinical Toxicology (13.2) ]. Advise patients about the potential risk of seizure. Use LYNKUET with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold.

The following clinically significant adverse reactions are described elsewhere in the labeling: Central Nervous System (CNS) Depressant Effect and Daytime Impairment [see Warnings and Precautions (5.1) ] Hepatic Transaminase Elevations [see Warnings and Precautions (5.2) ] Risk of Seizure [ see Warnings and Precautions (5.4) ] The most frequently reported (≥5%) adverse reactions were headache, fatigue, dizziness and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of LYNKUET was evaluated in three randomized, double-blind, placebo-controlled, multicenter clinical trials (OASIS 1, OASIS 2, OASIS 3 ) in 1420 women . In OASIS 1 and OASIS 2 combined, 793 women received LYNKUET or placebo for 12 weeks. After the first 12 weeks, 341 women randomized to LYNKUET continued to receive LYNKUET for another 14 weeks, with a total treatment duration of up to 26 weeks. In OASIS 1 and OASIS 2 combined, 349 women received placebo for the first 12 weeks and 348 women switched to LYNKUET for the next 14 weeks. In OASIS 3, 627 women received LYNKUET or placebo for up to 52 weeks to evaluate long-term safety [see Clinical Studies (14) ] . Common Adverse Reactions In OASIS 1 and 2 combined, through the first 12 weeks, commonly reported adverse reactions in the LYNKUET group (≥2% and greater than in placebo) were headache, fatigue, gastroesophageal reflux disease, dizziness, nausea, and somnolence. Similar adverse reactions were seen in OASIS 3. Table 2 shows adverse reactions reported in at least 2% of women and more commonly in women taking LYNKUET than placebo in OASIS 3. Table 2: Common Adverse Reactions Reported in ≥ 2% in LYNKUET and Greater than Placebo, Weeks 1-52 (OASIS 3) Adverse Reaction LYNKUET N=313 n (%) Placebo N=314 n (%) Headache 30 (9.6) 22 (7.0) Fatigue Includes asthenia. 23 (7.3) 9 (2.9) Dizziness Includes balance disorder, presyncope, vertigo, vertigo CNS origin, vertigo positional, and vestibular neuronitis. 19 (6.1) 6 (1.9) Somnolence Includes lethargy. 16 (5.1) 4 (1.3) Abdominal pain Includes abdominal discomfort, abdominal pain lower/upper. 14 (4.5) 8 (2.5) Rash Includes dermatitis, urticaria. 13 (4.2) 5 (1.6) Diarrhea 12 (3.8) 3 (1.0) Muscle spasms Includes muscle tightness. 10 (3.2) 2 (0.6) Other clinically important adverse reactions: Seizure was reported in one patient (<0.1%) with a history of seizures in the clinical trials of LYNKUET. Adverse Reactions Leading to Discontinuation In OASIS 3, adverse reactions leading to treatment discontinuation (≥1% in LYNKUET and greater than placebo) were abdominal pain (1.6%), fatigue (1.6%), depression (1.6%) and headache (1.3%). Photosensitivity In the OASIS trials, mild to moderate events of photosensitivity occurred in 0.5% of patients receiving LYNKUET and 0.1% of patients receiving placebo. Onset of photosensitivity reactions ranged from day 1 to day 290. While discontinuation occurred in one patient, photosensitivity events in other patients resolved under continued treatment with LYNKUET [see Nonclinical Toxicology (13.2) ].

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of LYNKUET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Postmarketing cases of seizure have been reported in patients treated with LYNKUET.

Strong CYP3A4 Inhibitors and grapefruit (juice): Avoid concomitant use with LYNKUET. ( 7.1 ) Moderate CYP3A4 Inhibitors: Reduce LYNKUET dosage to 60 mg once daily. ( 2.3 , 7.1 )21 Strong and Moderate CYP3A4 Inducers: Avoid concomitant use with LYNKUET. ( 7.1 )

7.1 Effects of Other Drugs on LYNKUET Elinzanetant is primarily metabolized via CYP3A4 enzyme. Table 3 describes drug interactions where concomitant use of another drug affects LYNKUET. Table 3: Drug Interactions: Concomitant Use of Other Drugs Affect the Use of LYNKUET Strong and Moderate CYP3A4 Inhibitors See www.fda.gov/CYPandTransporterInteractingDrugs for examples of strong and moderate CYP3A4 inhibitors, and CYP3A4 inducers. Prevention or Management Strong CYP3A4 Inhibitors and grapefruit (juice): Avoid concomitant use. Moderate CYP3A4 Inhibitors: Reduce the LYNKUET dosage [see Dosage and Administration (2.2) ]. Clinical Effect(s) Strong and moderate CYP3A4 inhibitors increase elinzanetant exposure, which may increase the risk of LYNKUET-associated adverse reactions [see Clinical Pharmacology (12.3) ]. Strong and Moderate CYP3A4 Inducers Prevention or Management Strong and moderate CYP3A4 inducers: Avoid concomitant use. Clinical Effect(s) Strong and moderate CYP3A4 inducers decrease elinzanetant exposure, which may reduce the effectiveness of LYNKUET.

7.2 Effects of LYNKUET on Other Drugs CYP3A4 Substrates Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions. See www.fda.gov/CYPandTransporterInteractingDrugs for examples of CYP3A4 substrates. Elinzanetant is a weak inhibitor of CYP3A4. Concomitant use of LYNKUET increases exposure of CYP3A4 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

End Stage Renal Disease with or without hemodialysis: Not recommended. ( 8.6 ) Moderate to Severe Hepatic Impairment: Not recommended. ( 8.7 )

8.1 Pregnancy Risk Summary LYNKUET is contraindicated in pregnancy [see Contraindications (4) ]. If pregnancy occurs during the use of LYNKUET, discontinue treatment. Based on findings from animal reproduction studies, LYNKUET may cause pregnancy loss or stillbirth but not fetal malformations when administered during pregnancy. There are no data on the use of LYNKUET in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in rats, an increase in total litter loss or stillbirth and a decrease of neonatal pup viability was observed within the range of human therapeutic exposure when dams were treated orally throughout gestation and lactation [i.e., gestation day 6 to lactation day 21]. There was an increase in percentage of pre- and post-implantation embryo loss and decrease in fetal body weights at 16-fold the human therapeutic exposure when rat dams were treated orally prior to mating and through the early embryonic period [i.e., 22 days before mating to post-coitum day 6]. In rabbits, there was marked body weight loss and decreased food consumption in dams treated orally during gestation day 7 to 19 at doses equivalent to human therapeutic exposure (see Data ). Data Animal Data In a fertility and early embryonic development study in female rats, once daily oral doses of elinzanetant were administered 22 days before mating through post-coitum day 6. Increased percentage of pre-implantation and post-implantation embryo loss, resulting in reduced litter size, and lower fetal body weights were seen at the dose of 100 mg/kg/day (14-fold the AUC (0-24) at the human therapeutic dose). These effects were not observed following dosing at 25 mg/kg/day (3-fold the AUC (0-24) at the human therapeutic dose). In an embryo-fetal development study in pregnant rats, once daily oral doses of elinzanetant were administered throughout organogenesis from gestation day 6 to 17. No evidence of embryo-fetal lethality or teratogenicity occurred at doses ≤100 mg/kg/day (23-fold the AUC (0-24) at the human therapeutic dose) and no maternal toxicity occurred at doses ≤25 mg/kg/day (7-fold the AUC (0-24) at the human therapeutic dose). In an embryo-fetal development study in pregnant rabbits, twice daily oral doses of elinzanetant were administered throughout organogenesis from gestation day 7 to 19. Maternal toxicity in the form of marked body weight loss and decreased food consumption leading to early sacrifice in 4 out of 27 females was observed at the highest tested dose of 140 mg/kg/day (equivalent to the AUC (0-24) at the human therapeutic dose). No evidence of embryo-fetal lethality or teratogenicity occurred in fetuses of surviving dams at doses ≤140 mg/kg/day (equivalent to the AUC (0-24) at the human therapeutic dose). In a pre- and post-natal development study in rats, once daily oral doses of elinzanetant were administered from gestation day 6 to lactation day 21. A higher incidence of still born pups, an increase in total litter loss, a decrease in pup viability between postnatal days 0 and 4, and an increase in the number of neonatal pups without milk in the stomach were observed at a dose of ≥5 mg/kg/day (equivalent to the AUC (0-24) at the human therapeutic dose).

8.2 Lactation Risk Summary There are no data on the presence of elinzanetant or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Elinzanetant is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data ). Data Animal Data Following administration of radiolabeled elinzanetant to lactating rats, approximately 6% of the elinzanetant dose was excreted in the milk. Principle human metabolites of elinzanetant were also detected in the plasma of pups from rat dams that were dosed once daily orally during pregnancy and lactation at ≥1.5 mg/kg/day (elinzanetant AUC (0-24) below the range of human therapeutic exposure).

8.3 Females and Males of Reproductive Potential Based on findings from animal reproduction studies, LYNKUET may cause pregnancy loss or stillbirth when administered during pregnancy. Fetal malformations were not observed in those studies [see Use in Specific Populations (8.1) ]. Pregnancy Testing Exclude pregnancy before initiating treatment with LYNKUET. Perform pregnancy testing if pregnancy is suspected during treatment with LYNKUET, and discontinue treatment if pregnancy is confirmed [see Contraindications (4) and Warnings and Precautions (5.3) ] . Contraception Females Pregnancy should be prevented in women of reproductive potential by using effective contraception during and for 2 weeks after stopping treatment because LYNKUET can cause pregnancy loss or stillbirth [see Use in Specific Populations (8.1) ].

8.4 Pediatric Use The efficacy and safety of LYNKUET in pediatric patients have not been established, and LYNKUET is not indicated in this population.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical trials utilizing LYNKUET to determine whether those over 65 years of age differ from younger women in their response to LYNKUET.

8.6 Renal Impairment No dose adjustment is required for patients with mild to severe [estimated glomerular filtration rate (eGFR) 15 to < 90 mL/min] renal impairment. The effect of end-stage renal disease (eGFR <15 mL/min) (with or without hemodialysis) on the pharmacokinetics of LYNKUET has not been studied [see Clinical Pharmacology (12.3) ] .

8.7 Hepatic Impairment No dose adjustment is required in patients with mild (Child-Pugh A) hepatic impairment. Moderate (Child-Pugh B) hepatic impairment increased the exposure of LYNKUET. LYNKUET has not been studied in individuals with severe (Child-Pugh C) hepatic impairment. LYNKUET is not recommended in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) ] .

LYNKUET is a neurokinin 1 (NK1) and neurokinin 3 (NK3) receptor antagonist. Inhibition of Substance P and Neurokinin B through antagonism of NK1 and NK3 receptor signaling on kisspeptin/neurokinin B/dynorphin (KNDy) neurons can modulate neuronal activity in thermoregulation associated with hot flashes. Elinzanetant has higher affinity for human NK1 receptors (pKi values of 8.7 to 10.2) and NK3 receptors (pKi values of 8.0 to 8.8) than for human NK2 receptors (pKi values of approximately 6.0).